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  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D205/00—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom
  • C07D205/02—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings
  • C07D205/06—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
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  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
  • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
  • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
  • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
  • C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
  • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
  • C07D403/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing aromatic rings
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  • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
  • C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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  • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
  • C07D409/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms

Definitions

• Marijuana Cannabis sativa L.
• Marijuana Cannabis sativa L.
• a major active ingredient in marijuana and hashish has been determined to be ⁇ 9 -tetrahydrocannabinol ( ⁇ 9 -THC).
• ⁇ 9 -THC ⁇ 9 -tetrahydrocannabinol
• CB1 and CB2 G-protein coupled receptors
• the CB1 receptor is primarily found in the central and peripheral nervous systems and to a lesser extent in several peripheral organs.
• the CB2 receptor is found primarily in lymphoid tissues and cells.
• CB1 modulators characterized as an inverse agonista or an antagonists, N-(1-piperidinyl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methylpyrazole-3-carboxamide (SR141716A), and 3-(4-chlorophenyl-N′-(4-chlorophenyl)sulfonyl-N-methyl-4-phenyl-4,5-dihydro-1H-pyrazole-1-carboxamide (SLV-319), in clinical trials for treatment of eating disorders and/or smoking cessation at this time.
• CB1 modulators characterized as an inverse agonista or an antagonists
• SLV-319 3-(4-chlorophenyl-N′-(4-chloropheny
• cannabinoid receptor modulating compounds are disclosed in U.S. Pat. Nos. 4,973,587, 5,013,837, 5,081,122, 5,112,820, 5,292,736, and 5,532,237, and PCT publications WO 97/29079, WO 98/37061, WO 99/02499, WO 00/10967, WO 00/10968, WO 01/58869, WO 01/70700, WO 02/076949, WO 03/026647, WO 03/026648, WO 03/027069, WO 03/027076, WO 03/027114, and WO 03/077847.
• the present invention is concerned with substituted 3-alkyl and 3-alkenyl azetidine derivatives of general formula I:
• the invention is concerned with the use of these novel compounds to selectively antagonize the Cannabinoid-1 (CB1) receptor.
• compounds of the present invention are useful as centrally acting drugs in the treatment of psychosis, memory deficits, cognitive disorders, migraine, neuropathy, neuro-inflammatory disorders including multiple sclerosis and Guillain-Barre syndrome and the inflammatory sequelae of viral encephalitis, cerebral vascular accidents, and head trauma, anxiety disorders, stress, epilepsy, Parkinson's disease, movement disorders, and schizophrenia.
• the compounds are also useful for the treatment of substance abuse disorders, particularly to opiates, alcohol, marijuana, and nicotine, including smoking cessation.
• the compounds are also useful for the treatment of obesity or eating disorders associated with excessive food intake and complications associated therewith, including left ventricular hypertrophy.
• the compounds are also useful for the treatment of constipation and chronic intestinal pseudo-obstruction.
• the compounds are also useful for the treatment of cirrhosis of the liver.
• the compounds are also useful for the treatment of asthma.
• the present invention is also concerned with treatment of these conditions, and the use of compounds of the present invention for manufacture of a medicament useful in treating these conditions.
• the present invention is also concerned with treatment of these conditions through a combination of compounds of formula I and other currently available pharmaceuticals.
• the invention is also concerned with pharmaceutical formulations comprising one of the compounds as an active ingredient.
• the invention is further concerned with processes for preparing the compounds of this invention.
• Ar is selected from:
• Ar is selected from:
• Ar is selected from:
• Ar is selected from: phenyl, 4-chlorophenyl, 3-cyanophenyl, 4-cyanophenyl, 4-trifluoromethylphenyl, 4-chloro-3-iodophenyl, 4-bromophenyl, 3-methylsulfonylphenyl, 4-fluorophenyl, and 4-methylphenyl.
• Ar is selected from phenyl, and pyridyl; wherein phenyl and pyridyl are unsubstituted or substituted with one or two substituents independently selected from: halogen, methyl, trifluoromethyl, cyano, —S(O) n R 10 .
• Ar is selected from:
• Ar is selected from:
• Ar is 4-chlorophenyl.
• R 4 is selected from:
• R 4 is selected from:
• R 4 is selected from:
• R 4 is selected from:
• R 4 is selected from:
• R 4 is selected from:
• R 4 is selected from:
• R 4 is selected from:
• R 4 is selected from:
• R 4 is selected from:
• R 5 , R 6 , R 7 , and R 8 are each independently selected from: hydrogen, C 1-6 alkyl, unsubstituted or substituted with R b , and C 2-6 alkenyl, unsubstituted or substituted with R b .
• R 5 , R 6 , R 7 , and R 8 are each independently selected from: hydrogen, methyl and C 2 alkenyl.
• one of R 5 , R 6 , R 7 , and R 8 is methyl and the other three are each hydrogen.
• R 5 , R 6 , R 7 , and R 8 are each hydrogen.
• Z is selected from hydrogen, hydroxy, fluoro, methyl, and —N(R 11 )(R 12 ), and Z 1 is selected from:
• Z is selected from hydrogen, hydroxy, fluoro, methyl, and —NH 2
• Z 1 is selected from:
• Z is selected from hydrogen and hydroxy, and Z 1 is:
• Z is selected from hydrogen and hydroxy, and Z 1 is:
• Z is hydrogen
• Z 1 is:
• Y is selected from:
• Y is selected from:
• Y is selected from:
• Y is selected from:
• Y is hydrogen
• X′ is selected from:
• X′ is selected from:
• X′ is selected from:
• X′ is selected from:
• X′ is selected from:
• X′ is selected from:
• X′ is selected from:
• Z and Z 1 together form:
• Z and Z 1 together form:
• Z and Z 1 together form:
• Z and Z 1 together form:
• X is selected from:
• X is selected from:
• X is selected from:
• X is selected from:
• X is selected from:
• X is selected from:
• X is selected from:
• R 1 is selected from:
• R 1 is selected from:
• R 1 is selected from
• R 1 is selected from:
• R 1 is selected from:
• R 1 is 3,5-difluorophenyl.
• R 1 is:
• R 1 is selected from:
• R 2 and R 3 together with the carbon atom to which they are attached, form a carbonyl group.
• R 2 and R 3 together with the carbon atom to which they are attached, form a 3 to 7 membered carbocyclic ring system.
• R 2 and R 3 together with the carbon atom to which they are attached, form a 3, 4, or 5-membered carbocyclic ring.
• R 2 and R 3 together with the carbon atom to which they are attached, form a 4-membered carbocyclic ring.
• R 2 and R 3 are each independently selected from:
• R 2 and R 3 are each independently selected from:
• R 2 is selected from:
• R 2 is selected from:
• R 2 and R 3 are each fluoro.
• R 9 is selected from: hydrogen, C 1-6 alkyl, and C 2-6 alkenyl, straight chain or branched, unsubstituted or substituted with one to three halogen atoms.
• R 9 is selected from: hydrogen, and C 1-6 alkyl, straight chain or branched, unsubstituted or substituted with one to three halogen atoms.
• R 9 is selected from: hydrogen, C 1-6 alkyl, straight chain or branched, and trifluoromethyl.
• R 9 is selected from: hydrogen and methyl.
• R 10 is selected from:
• R 10 is selected from:
• R 10 is selected from:
• R 11 and R 12 together with the atom(s) to which they are attached form a heterocyclic ring of 4 to 7 members containing 0-2 additional heteroatoms independently selected from oxygen, sulfur and N—R 9 .
• R 11 and R 12 together with the atom(s) to which they are attached form a heterocyclic ring of 5 to 6 members.
• R 11 and R 12 are each independently selected from:
• R 11 and R 12 are each independently selected from:
• R 11 and R 12 are each independently selected from:
• R 11 and R 12 are each independently selected from:
• each R a is independently selected from:
• each R a is independently selected from
• each R a is independently selected from:
• each R b is independently selected from:
• each R b is independently selected from:
• each R b is independently selected from:
• each R b is independently selected from:
• each R c is independently selected from:
• each R c is independently selected from:
• each R c is independently selected from:
• each R c is independently selected from:
• each R c is independently selected from:
• each R d is independently selected from:
• each R d is independently selected from:
• each R d is independently selected from:
• R e and R f together with the atom(s) to which they are attached form a heterocyclic ring of 4 to 7 members containing 0-2 additional heteroatoms independently selected from oxygen, sulfur and N—R 9 .
• R e and R f together with the atom(s) to which they are attached form a heterocyclic ring of 5 to 6 members.
• R e and R f are each independently selected from:
• R e and R f are each independently selected from:
• R e and R f are each independently selected from:
• R 2 and R 3 are not:
• R 2 and R 3 are not:
• Alkyl as well as other groups having the prefix “alk”, such as alkoxy, alkanoyl, means carbon chains which may be linear or branched or combinations thereof.
• alkyl groups include methyl, ethyl, n-propyl, isopropyl, butyl, isobutyl, sec- and tert-butyl, pentyl, hexyl, heptyl, octyl, nonyl, and the like.
• Alkenyl means carbon chains which contain at least one carbon-carbon double bond, and which may be linear or branched or combinations thereof. Examples of alkenyl include vinyl, alkyl, isopropenyl, pentenyl, hexenyl, heptenyl, 1-propenyl, 2-butenyl, 2-methyl-2-butenyl, and the like.
• Alkynyl means carbon chains which contain at least one carbon-carbon triple bond, and which may be linear or branched or combinations thereof. Examples of alkynyl include ethynyl, propargyl, 3-methyl-1-pentynyl, 2-heptynyl and the like.
• Cycloalkyl means mono- or bicyclic or bridged saturated carbocyclic rings, each having from 3 to 10 carbon atoms.
• Examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooxtyl, tetrahydronaphthyl, decahydronaphthyl, and the like.
• Aryl means mono- or bicyclic aromatic rings containing only carbon atoms. Examples of aryl include phenyl, naphthyl, and the like.
• Heteroaryl means a mono- or bicyclic aromatic ring containing at least one heteroatom selected from N, O and S, with each ring containing 5 to 6 atoms.
• heteroaryl include pyrrolyl, isoxazolyl, isothiazolyl, pyrazolyl, pyridyl, oxazolyl, oxadiazolyl, thiadiazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, triazinyl, thienyl, pyrimidyl, pyridazinyl, pyrazinyl, benzoxazolyl, benzothiazolyl, benzimidazolyl, benzofuranyl, benzothiophenyl, benzothiazolyl, furo(2,3-b)pyridyl, quinolyl, indolyl, isoquinolyl, oxazolidinyl,
• Cycloheteroalkyl means mono- or bicyclic or bridged saturated rings containing at least one heteroatom selected from N, S and O, each of said ring having from 3 to 10 atoms in which the point of attachment may be carbon or nitrogen.
• Examples of “cycloheteroalkyl” include pyrrolidinyl, piperidinyl, piperazinyl, imidazolidinyl, pyranyl, tetrahydrofuranyl, morpholinyl, dioxanyl, oxanyl, azetidinyl, perhydroazepinyl, tetrahydrofuranyl, 1-thia-4-aza-cyclohexane (thiomorpholinyl), hexahydrothienopyridinyl, thienopyridinyl, azacycloheptyl, and the like.
• the term also includes partially unsaturated monocyclic rings that are not aromatic, such as 2- or 4-pyridones attached through the nitrogen or N-substituted-1H, 3H)-pyrimidine-2,4-diones (N-substituted uracils).
• the cycloheteroalkyl ring may be substituted on the ring carbons and/or the ring nitrogens.
• Halogen includes fluorine, chlorine, bromine and iodine.
• any variable e.g., R 1 , R d , etc.
• its definition on each occurrence is independent of its definition at every other occurrence. Also, combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.
• substituted shall be deemed to include multiple degrees of substitution by a named substitutent. Where multiple substituent moieties are disclosed or claimed, the substituted compound can be independently substituted by one or more of the disclosed or claimed substituent moieties, singly or plurally. By independently substituted, it is meant that the (two or more) substituents can be the same or different.
• Compounds of Formula I may contain one or more asymmetric centers and can thus occur as racemates and racemic mixtures, single enantiomers, diastereomeric mixtures and individual diastereomers. The present invention is meant to comprehend all such isomeric forms of the compounds of Formula I.
• Tautomers are defined as compounds that undergo rapid proton shifts from one atom of the compound to another atom of the compound. Some of the compounds described herein may exist as tautomers with different points of attachment of hydrogen. Such an example may be a ketone and its enol form known as keto-enol tautomers. The individual tautomers as well as mixture thereof are encompassed with compounds of Formula I.
• Compounds of the Formula I may be separated into diastereoisomeric pairs of enantiomers by, for example, fractional crystallization from a suitable solvent, for example MeOH or ethyl acetate or a mixture thereof.
• a suitable solvent for example MeOH or ethyl acetate or a mixture thereof.
• the pair of enantiomers thus obtained may be separated into individual stereoisomers by conventional means, for example by the use of an optically active amine as a resolving agent or on a chiral HPLC column.
• any enantiomer of a compound of the general Formula I may be obtained by stereospecific synthesis using optically pure starting materials or reagents of known configuration.
• crystalline forms for compounds of the present invention may exist as polymorphs and as such are intended to be included in the present invention.
• some of the compounds of the instant invention may form solvates with water or common organic solvents. Such solvates are encompassed within the scope of this invention.
• Racemic mixtures can be separated into their individual enantiomers by any of a number of conventional methods. These include chiral chromatography, derivatization with a chiral auxiliary followed by separation by chromatography or crystallization, and fractional crystallization of diastereomeric salts.
• salts derived from inorganic bases include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic salts, manganous, potassium, sodium, zinc, and the like. Particularly preferred are the ammonium, calcium, magnesium, potassium, and sodium salts.
• Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins, such as arginine, betaine, caffeine, choline, N,N′ -dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethyl-morpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, and the like.
• basic ion exchange resins such
• pharmaceutically acceptable salt further includes all acceptable salts such as acetate, lactobionate, benzenesulfonate, laurate, benzoate, malate, bicarbonate, maleate, bisulfate, mandelate, bitartrate, mesylate, borate, methylbromide, bromide, methylnitrate, calcium edetate, methylsulfate, camrsylate, mucate, carbonate, napsylate, chloride, nitrate, clavulanate, N-methylglucamine, citrate, ammonium salt, dihydrochloride, oleate, edetate, oxalate, edisylate, pamoate (embonate), estolate, palmitate, esylate, pantothenate, fumarate, phosphate/diphosphate, gluceptate, polygalacturonate, gluconate, salicylate, glutamate, stearate, glycolly
• Compounds of the present invention are modulators of the CB1 receptor.
• the compounds of structural formula I are antagonists or inverse agonists of the CB1 receptor.
• An “agonist” is a compound (hormone, neurotransmitter or synthetic compound) which binds to a receptor and mimics the effects of the endogenous regulatory compound, such as contraction, relaxation, secretion, change in enzyme activity, etc.
• An “antagonist” is a compound, devoid of intrinsic regulatory activity, which produces effects by interfering with the binding of the endogenous agonist or inhibiting the action of an agonist.
• An “inverse agonist” is a compound which acts on a receptor but produces the opposite effect produced by the agonist of the particular receptor.
• Compounds of this invention are modulators of the CB1 receptor and as such are useful as centrally acting drugs in the treatment of psychosis, memory deficits, cognitive disorders, migraine, neuropathy, neuro-inflammatory disorders including multiple sclerosis and Guillain-Barre syndrome and the inflammatory sequelae of viral encephalitis, cerebral vascular accidents, and head trauma, anxiety disorders, stress, epilepsy, Parkinson's disease, movement disorders, and schizophrenia.
• the compounds are also useful for the treatment of substance abuse disorders, particularly to opiates, alcohol, marijuana, and nicotine.
• the compounds are also useful for the treatment of obesity or eating disorders associated with excessive food intake and complications associated therewith, including left ventricular hypertrophy, as well as treating or preventing obesity in other mammalian species, including canines and felines.
• the compounds are also useful for the treatment of constipation and chronic intestinal pseudo-obstruction.
• the compounds are also useful for the treatment of cirrhosis of the liver.
• the compounds are also useful for the treatment of asthma.
• administering should be understood to mean providing a compound of the invention or a prodrug of a compound of the invention to the individual in need of treatment.
• the administration of the compound of structural formula I in order to practice the present methods of therapy is carried out by administering an effective amount of the compound of structural formula I to the mammalian patient in need of such treatment or prophylaxis.
• the need for a prophylactic administration according to the methods of the present invention is determined via the use of well known risk factors.
• the effective amount of an individual compound is determined, in the final analysis, by the physician or veterinarian in charge of the case, but depends on factors such as the exact disease to be treated, the severity of the disease and other diseases or conditions from which the patient suffers, the chosen route of administration other drugs and treatments which the patient may concomitantly require, and other factors in the physician's judgment.
• prophylactic or therapeutic dose of a compound of Formula I will, of course, vary with the nature of the severity of the condition to be treated and with the particular compound of Formula I and its route of administration. It will also vary according to the age, weight and response of the individual patient. In general, the daily dose range lie within the range of from about 0.001 mg to about 100 mg per kg body weight of a mammal, preferably 0.01 mg to about 50 mg per kg, and most preferably 0.1 to 10 mg per kg, in single or divided doses. On the other hand, it may be necessary to use dosages outside these limits in some cases.
• a suitable dosage range is from about 0.001 mg to about 100 mg in one embodiment from 0.01 mg to about 50 mg, and in another embodiment from 0.1 mg to 10 mg of a compound of Formula I per kg of body weight per day.
• a suitable dosage range is, e.g. from about 0.01 mg to about 1000 mg of a compound of Formula I per day. In one embodiment, the range is from about 0.1 mg to about 10 mg per day.
• the compositions are preferably provided in the form of tablets containing from 0.01 to 1,000 mg, preferably 0.01, 0.05, 0.1, 0.5, 1, 2.5, 5, 10, 15, 20, 25, 30, 40, 50, 100, 250, 500, 750 or 1000 milligrams of the active ingredient for the symptomatic adjustment of the dosage to the patient to be treated.
• compositions which comprises a compound of Formula I and a pharmaceutically acceptable carrier.
• composition is intended to encompass a product comprising the active ingredient(s), and the inert ingredient(s) (pharmaceutically acceptable excipients) that make up the carrier, as well as any product which results, directly or indirectly, from combination, complexation or aggregation of any two or more of the ingredients, or from dissociation of one or more of the ingredients, or from other types of reactions or interactions of one or more of the ingredients.
• the pharmaceutical compositions of the present invention encompass any composition made by admixing a compound of Formula I, additional active ingredient(s), and pharmaceutically acceptable excipients.
• Any suitable route of administration may be employed for providing a mammal, particularly a human or companion animal such as a dog or cat, with an effective dosage of a compound of the present invention.
• a mammal particularly a human or companion animal such as a dog or cat
• an effective dosage of a compound of the present invention for example, oral, rectal, topical, parenteral, ocular, pulmonary, nasal, and the like may be employed.
• Dosage forms include tablets, troches, dispersions, suspensions, solutions, capsules, creams, ointments, aerosols, and the like.
• compositions of the present invention comprise a compound of Formula I as an active ingredient or a pharmaceutically acceptable salt thereof, and may also contain a pharmaceutically acceptable carrier and optionally other therapeutic ingredients.
• pharmaceutically acceptable it is meant the carrier, diluent or excipient must be compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
• the compositions include compositions suitable for oral, rectal, topical, parenteral (including subcutaneous, intramuscular, and intravenous), ocular (ophthalmic), pulmonary (aerosol inhalation), or nasal administration, although the most suitable route in any given case will depend on the nature and severity of the conditions being treated and on the nature of the active ingredient. They may be conveniently presented in unit dosage form and prepared by any of the methods well-known in the art of pharmacy.
• the compounds of the present invention are conveniently delivered in the form of an aerosol spray presentation from pressurized packs or nebulizers.
• the compounds may also be delivered as powders which may be formulated and the powder composition may be inhaled with the aid of an insufflation powder inhaler device.
• the preferred delivery systems for inhalation are metered dose inhalation (MDI) aerosol, which may be formulated as a suspension or solution of a compound of Formula I in suitable propellants, such as fluorocarbons or hydrocarbons and dry powder inhalation (DPI) aerosol, which may be formulated as a dry powder of a compound of Formula I with or without additional excipients.
• MDI metered dose inhalation
• DPI dry powder inhalation
• Suitable topical formulations of a compound of formula I include transdermal devices, aerosols, creams, solutions, ointments, gels, lotions, dusting powders, and the like.
• the topical pharmaceutical compositions containing the compounds of the present invention ordinarily include about 0.005% to 5% by weight of the active compound in admixture with a pharmaceutically acceptable vehicle.
• Transdermal skin patches useful for administering the compounds of the present invention include those well known to those of ordinary skill in that art. To be administered in the form of a transdermal delivery system, the dosage administration will, of course, be continuous rather than intermittent throughout the dosage regimen.
• the compounds of Formula I can be combined as the active ingredient in intimate admixture with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques.
• the carrier may take a wide variety of forms depending on the form of preparation desired for administration, e.g., oral or parenteral (including intravenous).
• any of the usual pharmaceutical media may be employed, such as, for example, water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents and the like in the case of oral liquid preparations, such as, for example, suspensions, elixirs and solutions; or carriers such as starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents and the like in the case of oral solid preparations such as, for example, powders, capsules and tablets, with the solid oral preparations being preferred over the liquid preparations. Because of their ease of administration, tablets and capsules represent the most advantageous oral dosage unit form in which case solid pharmaceutical carriers are obviously employed. If desired, tablets may be coated by standard aqueous or nonaqueous techniques.
• the compounds of Formula I may also be administered by controlled release means and/or delivery devices such as those described in U.S. Pat. Nos. 3,845,770; 3,916,899; 3,536,809; 3,598,123; 3,630,200 and 4,008,719.
• compositions of the present invention suitable for oral administration may be presented as discrete units such as capsules (including timed release and sustained release formulations), pills, cachets, powders, granules or tablets each containing a predetermined amount of the active ingredient, as a powder or granules or as a solution or a suspension in an aqueous liquid, a non-aqueous liquid, an oil-in-water emulsion or a water-in-oil liquid emulsion, including elixirs, tinctures, solutions, suspensions, syrups and emulsions.
• Such compositions may be prepared by any of the methods of pharmacy but all methods include the step of bringing into association the active ingredient with the carrier which constitutes one or more necessary ingredients.
• compositions are prepared by uniformly and intimately admixing the active ingredient with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product into the desired presentation.
• a tablet may be prepared by compression or molding, optionally with one or more accessory ingredients.
• Compressed tablets may be prepared by compressing in a suitable machine, the active ingredient in a free-flowing form such as powder or granules, optionally mixed with a binder, lubricant, inert diluent, surface active or dispersing agent. Molded tablets may be made by molding in a suitable machine, a mixture of the powdered compound moistened with an inert liquid diluent.
• each tablet cachet or capsule contains from about 0.01 to 1,000 mg, particularly 0.01, 0.05, 0.1, 0.5, 1.0, 2.5, 3, 5, 6, 10, 15, 25, 30, 40, 50, 75, 100, 125, 150, 175, 180, 200, 225, 250, 500, 750 and 1,000 milligrams of the active ingredient for the symptomatic adjustment of the dosage to the patient to be treated.
• Additional suitable means of administration of the compounds of the present invention include injection, intravenous bolus or infusion, intraperitoneal, subcutaneous, intramuscular and topical, with or without occlusion.
• Exemplifying the invention is a pharmaceutical composition comprising any of the compounds described above and a pharmaceutically acceptable carrier. Also exemplifying the invention is a pharmaceutical composition made by combining any of the compounds described above and a pharmaceutically acceptable carrier. An illustration of the invention is a process for making a pharmaceutical composition comprising combining any of the compounds described above and a pharmaceutically acceptable carrier.
• the dose may be administered in a single daily dose or the total daily dosage may be administered in divided doses of two, three or four times daily. Furthermore, based on the properties of the individual compound selected for administration, the dose may be administered less frequently, e.g., weekly, twice weekly, monthly, etc. The unit dosage will, of course, be correspondingly larger for the less frequent administration.
• the dosage administration When administered via intranasal routes, transdermal routes, by rectal or vaginal suppositories, or through a continual intravenous solution, the dosage administration will, of course, be continuous rather than intermittent throughout the dosage regimen.
• Injectable Suspension mg/mL Compound of Formula I 10 Methylcellulose 5.0 Tween 80 0.5 Benzyl alcohol 9.0 Benzalkonium chloride 1.0 Water for injection to a total volume of 1 mL Capsule mg/capsule Compound of Formula I 25 Lactose Powder 573.5 Magnesium Stearate 1.5 600 Tablet mg/tablet Compound of Formula I 25 Microcrystalline Cellulose 415 Povidone 14.0 Pregelatinized Starch 43.5 Magnesium Stearate 2.5 500 Aerosol Per canister Compound of Formula I 24 mg Lecithin, NF Liq. Conc. 1.2 mg Trichlorofluoromethane, NF 4.025 g Dichlorodifluoromethane, NF 12.15 g
• Compounds of Formula I may be used in combination with other drugs that are used in the treatment/prevention/suppression or amelioration of the diseases or conditions for which compounds of Formula I are useful. Such other drugs may be administered, by a route and in an amount commonly used therefor, contemporaneously or sequentially with a compound of Formula I.
• a pharmaceutical composition containing such other drugs in addition to the compound of Formula I is preferred.
• the pharmaceutical compositions of the present invention include those that also contain one or more other active ingredients, in addition to a compound of Formula I.
• Examples of other active ingredients that may be combined with a compound of Formula I include, but are not limited to: antipsychotic agents, cognition enhancing agents, anti-migraine agents, anti-asthmatic agents, antiinflammatory agents, anxiolytics, anti-Parkinson's agents, anti-epileptics, anorectic agents, serotonin reuptake inhibitors, other anti-obesity agents, as well as antidiabetic agents, lipid lowering agents, and antihypertensive agents which may be administered separately or in the same pharmaceutical compositions.
• the present invention also provides a method for the treatment or prevention of a CB1 receptor modulator mediated disease, which method comprises administration to a patient in need of such treatment or at risk of developing a CB1 receptor modulator mediated disease of an amount of a CB1 receptor modulator and an amount of one or more active ingredients, such that together they give effective relief.
• a pharmaceutical composition comprising a CB1 receptor modulator and one or more active ingredients, together with at least one pharmaceutically acceptable carrier or excipient.
• a CB 1 receptor modulator and one or more active ingredients for the manufacture of a medicament for the treatment or prevention of a CB1 receptor modulator mediated disease.
• a product comprising a CB1 receptor modulator and one or more active ingredients as a combined preparation for simultaneous, separate or sequential use in the treatment or prevention of CB1 receptor modulator mediated disease.
• Such a combined preparation may be, for example, in the form of a twin pack.
• a compound of the present invention may be used in conjunction with other anorectic agents.
• the present invention also provides a method for the treatment or prevention of eating disorders, which method comprises administration to a patient in need of such treatment an amount of a compound of the present invention and an amount of an anorectic agent, such that together they give effective relief.
• Suitable anorectic agents of use in combination with a compound of the present invention include, but are not limited to, aminorex, amphechloral, amphetamine, benzphetainine, chlorphentermine, clobenzorex, cloforex, clominorex, clortermine, cyclexedrine, dexfenfluramine, dextroamphetamine, diethylpropion, diphemethoxidine, N-ethylamphetamine, fenbutrazate, fenfluramine, fenisorex, fenproporex, fludorex, fluminorex, furfurylmethylamphetamine, levamfetamine, levophacetoperane, mazindol, mefenorex, metamfepramone, methamphetamine, norpseudoephedrine, pentorex, phendimetrazine, phenmetrazine, phentermine,
• a particularly suitable class of anorectic agent are the halogenated amphetamine derivatives, including chlorphentermine, cloforex, clortermine, dexfenfluramine, fenfluramine, picilorex and sibutramine; and pharmaceutically acceptable salts thereof
• Particularly preferred halogenated amphetamine derivatives of use in combination with a compound of the present invention include: fenfluramine and dexfenfluramine, and pharmaceutically acceptable salts thereof.
• the present invention also provides a method for the treatment or prevention of obesity, which method comprises administration to a patient in need of such treatment an amount of a compound of the present invention and an amount of another agent useful in treating obesity and obesity-related conditions, such that together they give effective relief.
• Suitable agents of use in combination with a compound of the present invention include, but are not limited to:
• anti-diabetic agents such as (1) PPAR ⁇ agonists such as glitazones (e.g. ciglitazone; darglitazone; englitazone; isaglitazone (MCC-555); pioglitazone; rosiglitazone; troglitazone; BRL49653; CLX-0921; 5-BTZD, and GW-0207, LG-100641, and LY-300512, and the like and compounds disclosed in WO97/10813, 97/27857, 97/28115, 97/28137, 97/27847, 03/000685, 03/027112, 03/035602, 03/048130, 03/055867, and the like; (2) biguanides such as buformin; metformin; and phenformin, and the like; (3) protein tyrosine phosphatase-1B (PTP-1B) inhibitors, such as ISIS 113715, and those disclosed in WO
• lipid lowering agents such as (1) bile acid sequestrants such as, cholestyramine, colesevelem, colestipol, dialkylaminoalkyl derivatives of a cross-linked dextran; Colestid®; LoCholest®; and Questran®, and the like; (2) HMG-CoA reductase inhibitors such as atorvastatin, itavastatin, fluvastatin, lovastatin, pravastatin, rivastatin, rosuvastatin, simvastatin, and ZD-4522, and the like and compounds disclosed in WO 03/033481; (3) HMG-CoA synthase inhibitors; (4) cholesterol absorption inhibitors such as stanol esters, beta-sitosterol, sterol glycosides such as tiqueside; and azetidinones such as ezetilibe, and the like; (5) acyl coenzyme A -cholesterol acyl transfer
• anti-hypertensive agents such as (1) diuretics, such as thiazides, including chlorthalidone, chlorthiazide, dichlorophenamide, hydroflumethiazide, indapamide, and hydrochlorothiazide; loop diuretics, such as bumetanide, ethacrynic acid, furosemide, and torsemide; potassium sparing agents, such as amiloride, and triamterene; and aldosterone antagonists, such as spironolactone, epirenone, and the like; (2) beta-adrenergic blockers such as acebutolol, atenolol, betaxolol, bevantolol, bisoprolol, bopindolol, carteolol, carvedilol, celiprolol, esmolol, indenolol, metaprolol, nadolol, nebivolol
• anti-obesity agents such as (1) 5HT (serotonin) transporter inhibitors, such as paroxetine, fluoxetine, fenfluramine, fluvoxamine, sertraline, and imipramine, and those disclosed in WO 03/00663; (2) NE (norepinephrine) transporter inhibitors, such as GW 320659, despiramine, talsupram, and nomifensine; (3) CB1 (cannabinoind-1 receptor) antagonist/inverse agonists, such as rimonabant (Sanofi Synthelabo), SR-147778 (Sanofi Synthelabo), BAY 65-2520 (Bayer), and SLV 319 (Solvay), and those disclosed in U.S.
• 5HT serotonin
• NE neuropeptidephrine transporter inhibitors
• GW 320659 despiramine, talsupram, and nomifensine
• H3 (histamine H 3 ) antagonist/inverse agonists such as thioperamide, 3-(1H-imidazol-4-yl)propyl N-(4-pentenyl)carbamate), clobenpropit, iodophenpropit, imoproxifan, GT2394 (Gliatech), and A331440, and those disclosed in WO 02/15905; and O-[3-(1H-imidazol-4-yl)propanol]carbamates (Kiec-Kononowicz, K.
• MCH 1 R melanin-concentrating hormone 1 receptor antagonists
• T-226296 Takeda
• SNP-7941 Spaptic
• WO 02/051809 WO 01/82925
• WO 01/87834 WO 02/051809
• WO 02/06245 WO 02/076929
• WO 02/076947 WO 02/04433
• WO 02/51809 WO 02/083134
• WO 02/094799 WO 03/004027, WO 03/13574, WO 03/15769, WO 03/028641, WO 03/035624, WO 03/033476, WO 03/033480; and Japanese Patent Application Nos.
• NPY1 neuropeptide Y Y1
• JP 13226269, and JP 1437059 MCH 2 R (melanin concentrating hormone 2R) agonist/antagonists
• MCH 2 R melanin concentrating hormone 2R
• NPY1 neuropeptide Y Y1 antagonists, such as BIBP3226, J-115814, BIBO 3304, LY-357897, CP-671906, and GI-264879A; and those disclosed in U.S. Pat. No.
• NPY5 neuropeptide Y Y5
• NPY5 neuropeptide Y Y5
• NPY5 neuropeptide Y Y5 antagonists, such as 152,804, GW-569180A, GW-594884A, GW-587081X, GW-548118X; FR 235,208; FR226928, FR 240662, FR252384; 1229U91, GI-264879A, CGP71683A, LY-377897, LY366377, PD-160170, SR-120562A, SR-120819A, JCF-104, and H409/22; and those compounds disclosed in U.S.
• WO 97/19682 WO 97/20820, WO 97/20821, WO 97/20822, WO 97/20823, WO 98/27063, WO 00/107409, WO 00/185714, WO 00/185730, WO 00/64880, WO 00/68197, WO 00/69849, WO 01/09120, WO 01/14376, WO 01/85714, WO 01/85730, WO 01/07409, WO 01/02379, WO 01/02379, WO 01/23388, WO 01/23389, WO 01/44201, WO 01/62737, WO 01/62738, WO 01/09120, WO 02/20488, WO 02/22592, WO 02/48152, WO 02/49648, WO 02/051806, WO 02/094789, WO 03/009845, WO 03/014083, WO 03/0228
• leptin such as recombinant human leptin (PEG-OB, Hoffman La Roche) and recombinant methionyl human leptin (Amgen);
• leptin derivatives such as those disclosed in U.S. Pat. Nos.
• opioid antagonists such as nalmefene (Revex®), 3-methoxynaltrexone, naloxone, and naltrexone; and those disclosed in WO 00/21509; (13) orexin antagonists, such as SB-334867-A; and those disclosed in WO 01/96302, WO 01/68609, WO 02/44172, WO 02/51232, WO 02/51838, WO 02/089800, WO 02/090355, WO 03/023561, WO 03/032991, WO 03/037847; (14) BRS3 (bombesin receptor
• CNTF ciliary neurotrophic factors
• GI-181771 Gaxo-SmithKline
• SR146131 Sanofi Synthelabo
• butabindide butabindide
• PD170,292, PD 149164 Pfizer
• CNTF derivatives such as axokine (Regeneron); and those disclosed in WO 94/09134, WO 98/22128, and WO 99/43813
• GHS growth hormone secretagogue receptor
• NN703, hexarelin MK-0677, SM-130686, CP424,391, L-692,429 and L-163,255, and those disclosed in U.S.
• GLP-1 glucagon-like peptide 1 agonists
• Topiramate Topimax®
• phytopharm compound 57 CP 644,673
• ACC2 acetyl-CoA carboxylase-2
• ⁇ 3 beta adrenergic receptor 3) agonists, such as AD9677/TAK677 (Dainippon/Takeda), CL-316,243, SB 418790, BRL-37344, L-796568, BMS-196085, BRL-35135A, CGP12177A, BTA-243, GW 427353, Trecadrine, Zeneca D7114, N-5984 (Nisshin Kyorin), LY-377604 (Lilly), and SR 59119A, and those disclosed in U.S.
• DGAT1 diacylglycerol acyltransferase 1 inhibitors
• DGAT2 diacylglycerol acyltransferase 2inhibitors
• FAS fatty acid synthase
• PDE phosphodiesterase
• UCP-1 uncoupling protein 1
• 2, or 3 activators such as phytanic acid, 4-[(E)-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-napthalenyl)-1-propenyl]benzoic acid (TTNPB), and retinoic acid; and those disclosed in WO 99/00123; (35) acyl-estrogens, such as oleoyl-estrone, disclosed in del Mar-Grasa, M.
• HSD-1 11 ⁇ HSD-1 (11-beta hydroxy steriod dehydrogenase type 1) inhibitors, such as BVT 3498, BVT 2733, 3-(1-adamantyl)-4-ethyl-5-(ethylthio)-4H-1,2,4-triazole, 3-(1-adamantyl)-5-(3,4,5-trimethoxyphenyl)-4-methyl-4H-1,2,4-triazole, 3-adamantanyl-4,5,6,7,8,9,10,11,12,3a-decahydro-1,2,4-triazolo[4,3-a][11]annulene, and those compounds disclosed in WO 01/90091, WO 01/90090, WO 01/90092 and WO 02/072084; (38) SCD-1 (stearoyl-CoA desaturase-1) inhibitor
• NPY5 antagonists of use in combination with a compound of the present invention include: 3-oxo-N-(5-phenyl-2-pyrazinyl)-spiro[isobenzofuran-1(3H),4′-piperidine]-1′-carboxamide, 3-oxo-N-(7-trifluoromethylpyrido[3,2-b]pyridin-2-yl)spiro-[isobenzofuran-1(3H),4′-piperidine]-1′-carboxamide, N-[5-(3-fluorophenyl)-2-pyrimidinyl]-3-oxospiro-[isobenzofuran-1(3H),4′-piperidine]-1′-carboxamide, trans-3′-oxo-N-5-phenyl-2-pyrimidinyl)spiro[cyclohexane-1,1′(3′H)-isobenzofuran]4-carboxamide, trans-3′-oxo-
• Specific DP-IV inhibitors of use in combination with a compound of the present invention are selected from:
• “Obesity” is a condition in which there is an excess of body fat. The operational definition of obesity is based on the Body Mass Index (BMI), calculated as body weight per height in meters squared (kg/m 2 ). “Obesity” refers to a condition whereby an otherwise healthy subject has a Body Mass Index (BMI) greater than or equal to 30 kg/m 2 , or a condition whereby a subject with at least one co-morbidity has a BMI greater than or equal to 27 kg/m 2 .
• An “obese subject” is an otherwise healthy subject with a Body Mass Index (BMI) greater than or equal to 30 kg/m 2 or a subject with at least one co-morbidity with a BMI greater than or equal to 27 kg/m 2 .
• a “subject at risk for obesity” is an otherwise healthy subject with a BMI of 25 kg/m 2 to less than 30 kg/m 2 or a subject with at least one co-morbidity with a BMI of 25 kg/m 2 to less than 27 kg/m 2 .
• a subject with at least one obesity-induced or obesity-related co-morbidity that requires weight reduction or that would be improved by weight reduction has a BMI greater than or equal to 25 kg/m 2 .
• an “obese subject” refers to a subject with at least one obesity-induced or obesity-related co-morbidity that requires weight reduction or that would be improved by weight reduction, with a BMI greater than or equal to 25 kg/m 2 .
• a “subject at risk of obesity” is a subject with a BMI of greater than 23 kg/m 2 to less than 25 kg/m 2 .
• obesity is meant to encompass all of the above definitions of obesity.
• Obesity-induced or obesity-related co-morbidities include, but are not limited to, diabetes, non-insulin dependent diabetes mellitus—type 2, impaired glucose tolerance, impaired fasting glucose, insulin resistance syndrome, dyslipidemia, hypertension, hyperuricacidemia, gout, coronary artery disease, myocardial infarction, angina pectoris, sleep apnea syndrome, Pickwickian syndrome, fatty liver; cerebral infarction, cerebral thrombosis, transient ischemic attack, orthopedic disorders, arthritis deformans, lumbodynia, emmeniopathy, and infertility.
• co-morbidities include: hypertension, hyperlipidemia, dyslipidemia, glucose intolerance, cardiovascular disease, sleep apnea, diabetes mellitus, and other obesity-related conditions.
• Treatment refers to the administration of the compounds of the present invention to reduce or maintain the body weight of an obese subject.
• One outcome of treatment may be reducing the body weight of an obese subject relative to that subject's body weight immediately before the administration of the compounds of the present invention.
• Another outcome of treatment may be preventing body weight regain of body weight previously lost as a result of diet, exercise, or pharmacotherapy.
• Another outcome of treatment may be decreasing the occurrence of and/or the severity of obesity-related diseases.
• the treatment may suitably result in a reduction in food or calorie intake by the subject, including a reduction in total food intake, or a reduction of intake of specific components of the diet such as carbohydrates or fats; and/or the inhibition of nutrient absorption; and/or the inhibition of the reduction of metabolic rate; and in weight reduction in patients in need thereof.
• the treatment may also result in an alteration of metabolic rate, such as an increase in metabolic rate, rather than or in addition to an inhibition of the reduction of metabolic rate; and/or in minimization of the metabolic resistance that normally results from weight loss.
• Prevention refers to the administration of the compounds of the present invention to reduce or maintain the body weight of a subject at risk of obesity.
• One outcome of prevention may be reducing the body weight of a subject at risk of obesity relative to that subject's body weight immediately before the administration of the compounds of the present invention.
• Another outcome of prevention may be preventing body weight regain of body weight previously lost as a result of diet, exercise, or pharmacotherapy.
• Another outcome of prevention may be preventing obesity from occurring if the treatment is administered prior to the onset of obesity in a subject at risk of obesity.
• Another outcome of prevention may be decreasing the occurrence and/or severity of obesity-related disorders if the treatment is administered prior to the onset of obesity in a subject at risk of obesity.
• Such treatment may prevent the occurrence, progression or severity of obesity-related disorders, such as, but not limited to, arteriosclerosis, Type II diabetes, polycystic ovarian disease, cardiovascular diseases, osteoarthritis, dermatological disorders, hypertension, insulin resistance, hypercholesterolemia, hypertriglyceridemia, and cholelithiasis.
• the obesity-related disorders herein are associated with, caused by, or result from obesity.
• obesity-related disorders include overeating and bulimia, hypertension, diabetes, elevated plasma insulin concentrations and insulin resistance, dyslipidemias, hyperlipidemia, endometrial, breast, prostate and colon cancer, osteoarthritis, obstructive sleep apnea, cholelithiasis, gallstones, heart disease, abnormal heart rhythms and arrhythmias, myocardial infarction, congestive heart failure, coronary heart disease, sudden death, stroke, polycystic ovarian disease, craniopharyngioma, the Prader-Willi Syndrome, Frohlich's syndrome, GH-deficient subjects, normal variant short stature, Turner's syndrome, and other pathological conditions showing reduced metabolic activity or a decrease in resting energy expenditure as a percentage of total fat-free mass, e.g, children with acute lymphoblastic leukemia.
• obesity-related disorders are metabolic syndrome, also known as syndrome X, insulin resistance syndrome, sexual and reproductive dysfunction, such as infertility, hypogonadism in males and hirsutism in females, gastrointestinal motility disorders, such as obesity-related gastro-esophageal reflux, respiratory disorders, such as obesity-hypoventilation syndrome (Pickwickian syndrome), cardiovascular disorders, inflammation, such as systemic inflammation of the vasculature, arteriosclerosis, hypercholesterolemia, hyperuricaemia, lower back pain, gallbladder disease, gout, and kidney cancer.
• the compounds of the present invention are also useful for reducing the risk of secondary outcomes of obesity, such as reducing the risk of left ventricular hypertrophy.
• the compounds of formula I are also useful for treating or preventing obesity and obesity-related disorders in cats and dogs.
• the term “mammal” includes companion animals such as cats and dogs.
• diabetes includes both insulin-dependent diabetes mellitus (IDDM, also known as type I diabetes) and non-insulin-dependent diabetes mellitus (NIDDM, also known as Type II diabetes).
• IDDM insulin-dependent diabetes mellitus
• NIDDM non-insulin-dependent diabetes mellitus
• Type I diabetes or insulin-dependent diabetes
• Type II diabetes is the result of an absolute deficiency of insulin, the hormone which regulates glucose utilization.
• Type II diabetes, or insulin-independent diabetes i.e., non-insulin-dependent diabetes mellitus
• Most of the Type II diabetics are also obese.
• the compounds of the present invention are useful for treating both Type I and Type II diabetes.
• the compounds are especially effective for treating Type II diabetes.
• the compounds of the present invention are also useful for treating and/or preventing gestational diabetes mellitus.
• a compound of the present invention may be used in conjunction with other anti-migraine agents, such as ergotamines or 5-HT 1 agonists, especially sumatriptan, naratriptan, zolmatriptan or rizatriptan.
• a compound of the present invention may be used in conjunction with other anti-depressant or anti-anxiety agents.
• Suitable classes of anti-depressant agents include norepinephrine reuptake inhibitors, selective serotonin reuptake inhibitors (SSRIs), monoamine oxidase inhibitors (MAOIs), reversible inhibitors of monoamine oxidase (RINAs), serotonin and noradrenaline reuptake inhibitors (SNRIs), corticotropin releasing factor (CRF) antagonists, ⁇ -adrenoreceptor antagonists, neurokinin-1 receptor antagonists and atypical anti-depressants.
• SSRIs selective serotonin reuptake inhibitors
• MAOIs monoamine oxidase inhibitors
• RINAs reversible inhibitors of monoamine oxidase
• SNRIs serotonin and noradrenaline reuptake inhibitors
• CRF corticotropin releasing factor
• Suitable norepinephrine reuptake inhibitors include tertiary amine tricyclics and secondary amine tricyclics.
• Suitable examples of tertiary amine tricyclics include: amitriptyline, clomipramine, doxepin, imipramine and trimipramine, and pharmaceutically acceptable salts thereof.
• Suitable examples of secondary amine tricyclics include: amoxapine, desipramine, maprotiline, nortriptyline and protriptyline, and pharmaceutically acceptable salts thereof.
• Suitable selective serotonin reuptake inhibitors include: fluoxetine, fluvoxamine, paroxetine, imipramine and sertraline, and pharmaceutically acceptable salts thereof.
• Suitable monoamine oxidase inhibitors include: isocarboxazid, phenelzine, tranylcypromine and selegiline, and pharmaceutically acceptable salts thereof.
• Suitable reversible inhibitors of monoamine oxidase include: moclobemide, and pharmaceutically acceptable salts thereof.
• Suitable serotonin and noradrenaline reuptake inhibitors of use in the present invention include: venlafaxine, and pharmaceutically acceptable salts thereof.
• Suitable CRF antagonists include those compounds described in International Patent Specification Nos. WO 94/13643, WO 94/13644, WO 94/13661, WO 94/13676 and WO 94/13677. Still further, neurokinin-1 (NK-1) receptor antagonists may be favorably employed with the CB1 receptor modulators of the present invention. NK-1 receptor antagonists of use in the present invention are fully described, for example, in U.S. Pat. Nos. 5,162,339, 5,232,929, 5,242,930, 5,373,003, 5,387,595, 5,459,270, 5,494,926, 5,496,833, 5,637,699; European Patent Publication Nos.
• Specific neurokinin-1 receptor antagonists of use in the present invention include: ( ⁇ )-(2R3R,2S3S)-N- ⁇ [2-cyclopropoxy-5-(trifluoromethoxy)-phenyl]methyl ⁇ -2-phenylpiperidin-3-amine; 2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-4-fluorophenyl)-4-(3-(5-oxo-1H,4H-1,2,4-triazolo)methyl)morpholine; aperpitant; CJ17493; GW597599; GW679769; R673; RO67319; R1124; R1204; SSR146977; SSR240600; T-2328; and T2763; or a pharmaceutically acceptable salt thereof.
• Suitable atypical anti-depressants include: bupropion, lithium, nefazodone, trazodone and viloxazine, and pharmaceutically acceptable salts thereof.
• Suitable classes of anti-anxiety agents include benzodiazepines and 5-HT 1A agonists or antagonists, especially 5-H 1A partial agonists, and corticotropin releasing factor (CRF) antagonists.
• Suitable benzodiazepines include: alprazolam, chlordiazepoxide, clonazepam, chlorazepate, diazepam, halazepam, lorazepam, oxazepam and prazepam, and pharmaceutically acceptable salts thereof.
• Suitable 5-HT 1A receptor agonists or antagonists include, in particular, the 5-HT 1A receptor partial agonists buspirone, flesinoxan, gepirone and ipsapirone, and pharmaceutically acceptable salts thereof.
• Suitable corticotropin releasing factor (CRF) antagonists include those previously discussed herein.
• substance abuse disorders includes substance dependence or abuse with or without physiological dependence.
• the substances associated with these disorders are: alcohol, amphetamines (or amphetamine-like substances), caffeine, cannabis, cocaine, hallucinogens, inhalants, marijuana, nicotine, opioids, phencyclidine (or phencyclidine-like compounds), sedative-hypnotics or benzodiazepines, and other (or unknown) substances and combinations of all of the above.
• the term “substance abuse disorders” includes drug withdrawal disorders such as alcohol withdrawal with or without perceptual disturbances; alcohol withdrawal delirium; amphetamine withdrawal; cocaine withdrawal; nicotine withdrawal; opioid withdrawal; sedative, hypnotic or anxiolytic withdrawal with or without perceptual disturbances; sedative, hypnotic or anxiolytic withdrawal delirium; and withdrawal symptoms due to other substances. It will be appreciated that reference to treatment of nicotine withdrawal includes the treatment of symptoms associated with smoking cessation.
• substance abuse disorders include substance-induced anxiety disorder with onset during withdrawal; substance-induced mood disorder with onset during withdrawal; and substance-induced sleep disorder with onset during withdrawal.
• compounds of structural formula I are useful for aiding in stopping consumption of tobacco and are useful in treating nicotine dependence and nicotine withdrawal.
• the compounds of formula I produce in consumers of nicotine, such as tobacco smokers, a total or partial abstinence from smoking. Further, withdrawal symptoms are lessened and the weight gain that generally accompanies quitting tobacco consumption is reduced or nonexistent.
• the compound of form I may be used in combination with a nicotine agonist or a partial nicotine agonist, or a monoamine oxidase inhibitor (MAOI), or another active ingredient demonstrating efficacy in aiding cessation of tobacco consumption; for example, an antidepressant such as bupropion, doxepine, ornortriptyline; or an anxiolytic such as buspirone or clonidine.
• a nicotine agonist or a partial nicotine agonist or a monoamine oxidase inhibitor (MAOI)
• MAOI monoamine oxidase inhibitor
• a combination of a conventional antipsychotic drug with a CB1 receptor modulator may provide an enhanced effect in the treatment of mania. Such a combination would be expected to provide for a rapid onset of action to treat a manic episode thereby enabling prescription on an “as needed basis”. Furthermore, such a combination may enable a lower dose of the antispychotic agent to be used without compromising the efficacy of the antipsychotic agent, thereby minimizing the risk of adverse side-effects.
• a yet further advantage of such a combination is that, due to the action of the CB1 receptor modulator, adverse side-effects caused by the antipsychotic agent such as acute dystonias, dyskinesias, akathesia and tremor may be reduced or prevented.
• the present invention also provides a method for the treatment or prevention of mania, which method comprises administration to a patient in need of such treatment or at risk of developing mania of an amount of a CB1 receptor modulator and an amount of an antipsychotic agent, such that together they give effective relief.
• a pharmaceutical composition comprising a CB1 receptor modulator and an antipsychotic agent, together with at least one pharmaceutically acceptable carrier or excipient.
• the CB1 receptor modulator and the antipsychotic agent may be present as a combined preparation for simultaneous, separate or sequential use for the treatment or prevention of mania.
• Such combined preparations may be, for example, in the form of a twin pack.
• a product comprising a CB1 receptor modulator and an antipsychotic agent as a combined preparation for simultaneous, separate or sequential use in the treatment or prevention of mania.
• the CB1 receptor modulator and the antipsychotic agent may be in the same pharmaceutically acceptable carrier and therefore administered simultaneously. They may be in separate pharmaceutical carriers such as conventional oral dosage forms which are taken simultaneously.
• the term “combination” also refers to the case where the compounds are provided in separate dosage forms and are administered sequentially. Therefore, by way of example, the antipsychotic agent may be administered as a tablet and then, within a reasonable period of time, the CB1 receptor modulator may be administered either as an oral dosage form such as a tablet or a fast-dissolving oral dosage form.
• a “fast-dissolving oral formulation” is meant, an oral delivery form which when placed on the tongue of a patient, dissolves within about 10 seconds.
• CB1 receptor modulators in combination with an antipsychotic agent in the treatment or prevention of hypomania.
• a combination of a conventional antipsychotic drug with a CB1 receptor modulator may provide an enhanced effect in the treatment of schizophrenic disorders. Such a combination would be expected to provide for a rapid onset of action to treat schizophrenic symptoms thereby enabling prescription on an “as needed basis”. Furthermore, such a combination may enable a lower dose of the CNS agent to be used without compromising the efficacy of the antipsychotic agent, thereby minimizing the risk of adverse side-effects.
• a yet further advantage of such a combination is that, due to the action of the CB1 receptor modulator, adverse side-effects caused by the antipsychotic agent such as acute dystonias, dyskinesias, akathesia and tremor may be reduced or prevented.
• schizophrenic disorders includes paranoid, disorganized, catatonic, undifferentiated and residual schizophrenia; schizophreniform disorder; schizoaffective disorder; delusional disorder; brief psychotic disorder; shared psychotic disorder; substance-induced psychotic disorder; and psychotic disorder not otherwise specified.
• schizophrenic disorders include self-injurious behavior (e.g. Lesch-Nyhan syndrome) and suicidal gestures.
• Suitable antipsychotic agents of use in combination with a CB1 receptor modulator include the phenothiazine, thioxanthene, heterocyclic dibenzazepine, butyrophenone, diphenylbutylpiperidine and indolone classes of antipsychotic agent.
• Suitable examples of phenothiazines include chlorpromazine, mesoridazine, thioridazine, acetophenazine, fluphenazine, perphenazine and trifluoperazine.
• Suitable examples of thioxanthenes include chlorprothixene and thiothixene.
• dibenzazepines include clozapine and olanzapine.
• An example of a butyrophenone is haloperidol.
• An example of a diphenylbutylpiperidine is pimozide.
• An example of an indolone is molindolone.
• Other antipsychotic agents include loxapine, sulpiride and risperidone.
• the antipsychotic agents when used in combination with a CB1 receptor modulator may be in the form of a pharmaceutically acceptable salt, for example, chlorpromazine hydrochloride, mesoridazine besylate, thioridazine hydrochloride, acetophenazine maleate, fluphenazine hydrochloride, flurphenazine enathate, fluphenazine decanoate, trifluoperazine hydrochloride, thiothixene hydrochloride, haloperidol decanoate, loxapine succinate and molindone hydrochloride.
• Perphenazine, chlorprothixene, clozapine, olanzapine, haloperidol, pimozide and risperidone are commonly used in a non-salt form.
• D3 dopamine receptor antagonist is the compound PNU-99194A.
• D4 dopamine receptor antagonist is PNU-101387.
• a muscarinic m1 receptor agonist is xanomeline.
• Another class of antipsychotic agent of use in combination with a CB1 receptor modulator is the 5-HT 2A receptor antagonists, examples of which include MDL100907 and fananserin.
• the serotonin dopamine antagonists SDAs which are believed to combine 5-HT 2A and dopamine receptor antagonist activity, examples of which include olanzapine and ziperasidone.
• NK-1 receptor antagonists may be favorably employed with the CB1 receptor modulators of the present invention.
• Preferred NK-1 receptor antagonists for use in the present invention are selected from the classes of compounds described previously.
• a combination of a conventional anti-asthmatic drug with a CB1 receptor modulator may provide an enhanced effect in the treatment of asthma, and may be used for the treatment or prevention of asthma, which method comprises administration to a patient in need of such treatment an amount of a compound of the present invention and an amount of an anti-asthmatic agent, such that together they give effective relief.
• Suitable anti-asthmatic agents of use in combination with a compound of the present invention include, but are not limited to: (a) VLA-4 antagonists such as natalizumab and the compounds described in U.S. Pat. No. 5,510,332, WO97/03094, WO97/02289, WO96/40781, WO96/22966, WO96/20216, WO96/01644, WO96/06108, WO95/15973 and WO96/31206; (b) steroids and corticosteroids such as beclomethasone, methylprednisolone, betamethasone, prednisone, dexamethasone, and hydrocortisone; (c) antihistamines (H1-histamine antagonists) such as bromopheniramine, chlorpheniramine, dexchlorpheniramine, triprolidine, clemastine, diphenhydramine, diphenylpyraline, tripelennamine, hydroxyzine,
• a combination of a conventional anti-constipation drug with a CB1 receptor modulator may provide an enhanced effect in the treatment of constipation or chronic intestinal pseudo-obstruction, and for use for the manufacture of a medicament for the treatment or prevention of constipation or chronic intestinal pseudo-obstruction.
• the present invention also provides a method for the treatment or prevention of constipation, which method comprises administration to a patient in need of such treatment an amount of a compound of the present invention and an amount of an anti-constipation agent, such that together they give effective relief.
• Suitable anti-constipation agents of use in combination with a compound of the present invention include, but are not limited to, osmotic agents, laxatives and detergent laxatives (or wetting agents), bulking agents, and stimulants; and pharmaceutically acceptable salts thereof.
• a particularly suitable class of osmotic agents include, but are not limited to sorbitol, lactulose, polyethylene glycol, magnesium, phosphate,and sulfate; and pharmaceutically acceptable salts thereof.
• a particularly suitable class of laxatives and detergent laxatives include, but are not limited to, magnesium, and docusate sodium; and pharmaceutically acceptable salts thereof.
• a particularly suitable class of bulking agents include, but are not limited to, psyllium, methylcellulose, and calcium polycarbophil; and pharmaceutically acceptable salts thereof.
• a particularly suitable class of stimulants include, but are not limited to, anthroquinones, and phenolphthalein; and pharmaceutically acceptable salts thereof.
• a combination of a conventional anti-cirrhosis drug with a CB1 receptor modulator may provide an enhanced effect in the treatment or prevention of cirrhosis of the liver, and for use for the manufacture of a medicament for the treatment or prevention of cirrhosis of the liver.
• the present invention also provides a method for the treatment or prevention of cirrhosis of the liver, which method comprises administration to a patient in need of such treatment an amount of a compound of the present invention and an anti-cirrhosis agent, such that together they give effective relief.
• Suitable anti-cirrhosis agents of use in combination with a compound of the present invention include, but are not limited to, corticosteroids, penicillamine, colchicine, interferon- ⁇ , 2-oxoglutarate analogs, prostaglandin analogs, and other anti-inflammatory drugs and antimetabolites such as azathioprine, methotrexate, leflunamide, indomethacin, naproxen, and 6-mercaptopurine; and pharmaceutically acceptable salts thereof.
• the method of treatment of this invention comprises a method of modulating the CB1 receptor and treating CB1 receptor mediated diseases by administering to a patient in need of such treatment a non-toxic therapeutically effective amount of a compound of this invention that selectively antagonizes the CB1 receptor in preference to the other CB or G-protein coupled receptors.
• terapéuticaally effective amount means the amount the compound of structural formula I that will elicit the biological or medical response of a tissue, system, animal or human that is being sought by the researcher, veterinarian, medical doctor or other clinician, which includes alleviation of the symptoms of the disorder being treated.
• the novel methods of treatment of this invention are for disorders known to those skilled in the art.
• the term “mammal” includes humans, and companion animals such as dogs and cats.
• the weight ratio of the compound of the Formula I to the second active ingredient may be varied and will depend upon the effective dose of each ingredient. Generally, an effective dose of each will be used. Thus, for example, when a compound of the Formula I is combined with a ⁇ -3 agonist the weight ratio of the compound of the Formula I to the ⁇ -3 agonist will generally range from about 1000:1 to about 1:1000, preferably about 200:1 to about 1:200. Combinations of a compound of the Formula I and other active ingredients will generally also be within the aforementioned range, but in each case, an effective dose of each active ingredient should be used.
• aq or aq. aqueous; BOC or boc: benzyloxycarbonyl; brine: saturated sodium chloride solution; Bu: butyl; DAST: diethylaminosulfur trifluoride; DBU: 1,8-diazabicyclo[5.4.0]undec-7-ene; DIBAL-H: diisobutyl aluminum hydride; DMAP: 4-dimethylaminopyridine; DMF: dimethylformamide; DMSO: dimethylsulfoxide; EDAC: 1-ethyl-3-(3,3-diethylaminopropyl)-carbodiimide hydrochloride; Et: ethyl; g or gm: gram; h or hr: hours; HOAc: acetic acid; HOBT: 1-hydroxybenzotriazole; HPLC: high pressure liquid chromatography; HPLC/MS: high pressure liquid chromatography/mass spectroscopy; in vacuo: rotoevapor
• the starting material is the commercially available 1-(dimethylphenyl)-3-hyroxyazetidine (Oakwood Products, Inc.).
• the benzhydryl group of 1 is removed by catalytic hydrogenation in an alcoholic solvent using a palladium-charcoal catalyst and 50 psi hydrogen to afford the aminoalcohol 2.
• the amino group of 2 can be selectively alkylated with an appropriately substituted alkyl bromide 3 in the presence of a base such as diisopropylethylamine in an aprotic solvent such as THF to afford 4.
• the hydroxy group of 4 can be oxidized under Swern conditions (oxalyl chloride, DMSO, Et3N, CH 2 Cl 2 ) to afford the appropriately substituted ketone 5.
• a ketene acetal is formed in situ by deprotonation of an appropriately substituted ester 6 with a strong base such as butyllithium or lithium hexamethyldisilamine in an aprotic solvent such as THF at ⁇ 78° C. This ketene acetal adds to the carbonyl group of 5 to afford the hydroxy ester 7.
• Activation of the hydroxy group of 7 with methanesulfonyl chloride or methanesulfonic anhydride in the presence of a base such as DMAP or pyridine/DBU effects elimination to afford the olefin 8.
• the olefin of 8 is selectively reduced to 9 using an agent such as sodium borohydride in a protic solvent like methanol.
• the ester of 9 is reduced to the corresponding alcohol 10 with a reagent such as lithium aluminum hydride in an aprotic solvent such as ether or THF.
• the hydroxy group of 10 is converted to the aldehyde 11 by oxidation under Swern conditions.
• reaction of the carbonyl group of 11 with a carbanion such as Grignard reagent or alkyllithium reagent in an aprotic solvent such as ether or THF at low temperatures affords the secondary alcohol 12.
• the hydroxy group of 12 may be oxidized to the ketone 13 under Swern conditions.
• Another carbanion (either the same or different from that used in the first step) is then added to the carbonyl group of 13 to form the tertiary hydroxy compound 14.
• Scheme 4 illustrates the case where R 2 and R 3 are the same. Reaction of the carbonyl group of ester 9 with an excess of a carbanion such as Grignard reagent or alkyllithium reagent in an aprotic solvent such as ether or THF at low temperatures affords the tertiary alcohol 14.
• a carbanion such as Grignard reagent or alkyllithium reagent in an aprotic solvent such as ether or THF
• the benzhydryl group of ester 16 is selectively removed by treatment with an activating agent such as 1-chloroethyl chloroformate in THF followed by solvolysis in a nucleophilic solvent such as methanol to afford the free amine 17.
• the amino group of 17 is alkylated with an appropriately substituted alkyl bromide in the presence of a mild base such as cesium carbonate in an aprotic solvent such as acetonitrile to afford 8.
• Reaction of the ester group of 8 with an excess of a carbanion such as an alkyllithium reagent in an aprotic solvent such as ether at low temperatures affords the tertiary alcohol 15.
• the benzhydryl group of ester 16 is removed and the olefin reduced by catalytic hydrogenation in an alcoholic solvent using a palladium-charcoal catalyst and 50 psi hydrogen to afford the aminoester 19.
• the amino group of 19 is alkylated with an appropriately substituted alkyl bromide in the presence of a mild base such as cesium carbonate in an aprotic solvent such as acetonitrile to afford 9.
• Reaction of the ester group of 9 with an excess of a carbanion such as an alkyllithium reagent in an aprotic solvent such as ether at low temperatures affords the tertiary alcohol 14.
• Scheme 8 depicts an alternative synthesis of 14.
• the benzhydryl group of ester 16 is removed and the olefin reduced by catalytic hydrogenation in an alcoholic solvent using a palladium-charcoal catalyst and 50 psi hydrogen to afford the aminoester 19.
• the amino group of 19 is reacted with an appropriately substituted ketone 20 in the presence of a reducing agent such as sodium triacetoxyborohydride in an aprotic solvent such as dichloroethane.
• Reaction of the ester group of 9 with an excess of a carbanion such as an alkyllithium or alkylcerium reagent in an aprotic solvent such as ether at low temperatures affords the tertiary alcohol 14.
• the starting material 21 is the commercially available 1-(tert-butoxycarbonyl)-azetidine-3-carboxylic acid (PepTech Corporation).
• the carboxy group of 21 is activated with a reagent such as EDAC (1-ethyl-3-(3,3-dimethylaminopropyl)carbodiimide hydrochloride) in the presence of N-methyl-O-methylhydroxylamine hydrochloride and HOBT in a solvent such as dichloromethane to afford amide 22.
• a reagent such as EDAC (1-ethyl-3-(3,3-dimethylaminopropyl)carbodiimide hydrochloride) in the presence of N-methyl-O-methylhydroxylamine hydrochloride and HOBT in a solvent such as dichloromethane to afford amide 22.
• Carbanions such as an appropriately substituted Grignard reagent add selectively to the amide carbonyl group of 22 to form the ketone 23.
• the tert-butoxycarbonyl group of 23 is removed with trifluoroacetic acid in dichloromethane to form the amine 24, which reacts with an appropriately substituted alkyl bromide in the presence of a mild base such as diisopropylethylamine in an aprotic solvent like CH 3 CN to afford the ketone 25.
• a carbanion is formed in situ by deprotonation of an appropriately substituted nitrile 26 with a strong base such as butyllithium in an aprotic solvent such as THF at ⁇ 78 ° C. This adds to the carbonyl group of 25 to afford the hydroxy nitrile 27.
• Activation of the hydroxy group of 7 with phosphorous oxychloride in the presence of a base such as pyridine effects elimination to afford the olefin 28.
• reducing agents such as diisobutylaluminum hydride in an aprotic solvent such as dichloromethane add selectively to the ester carbonyl of 8 to afford the alkylic alcohyl 29.
• Activation of the hydroxy group of 29 with methanesulfonic anhydride in the presence of a base such as pyridine forms and displacement of the mesylate with a nucleophile such as sodium cyanide in a solvent such as acetonitrile forms the nitrile 30.
• nitrite is deprotonated with a strong base such as LHMDS in an inert solvent such as THF at low temperatures and the resulting carbanion reacts with electrophiles such as an appropriately substituted alkyl iodide to afford the 31.
• Compound 31 may be subjected to a second round of deprotonation/alylation to form 28.
• the hydroxyl group of compound 14 reacts under treatment with HF-pyridine complex in a solvent such as dichloroethane at 40° C. to form the corresponding fluoride 35.
• a solvent such as dichloroethane at 40° C.
• the existing N-substituent may be removed by hydrogenation with a catalyst such as 10% Pd on charcoal to afford amine 36.
• the alkyl group may be replaced by alkylation with same or a differently substituted bromide 3 under conditions described in Scheme 7 to afford 35.
• the hydroxyl group of compound 14 can be eliminated by treatment with DAST (diethylaminosulfur trifluoride) in an inert solvent such as dichloroethane to form the olefin 37.
• DAST diethylaminosulfur trifluoride
• an inert solvent such as dichloroethane
• the existing N-substiutuent may be removed by 1-chloroethyl chloroformate to afford amine 39 and the alkyl group may be replaced by alkylation with same or a differently substituted bromide 3 under conditions described in Scheme 7 to afford 37.
• a carbanion such as tert-butylmagnesium bromide is added to the carbonyl group of compound 23 (Scheme 7) in an solvent such as THF to afford hydroxyl adduct 43.
• the tert-butoxycarbonyl group of 43 is removed with trifluoroacetic acid in dichloromethane to form the amine 44, which reacts with an appropriately substituted alkyl bromide in the presence of a mild base such as diisopropylethylamine or Cs 2 CO 3 in an aprotic solvent like CH 3 CN to afford the alcohol 45.
• R 1 is an appropriately substituted aryl group, such as 3,5-difluorophenyl or 3-bromo-5-fluorophenyl, that aryl group may be further modified as depicted in the following schemes.
• a good nucleophile such as the sodium or potassium salt of a thiol will displace one or both arylfluorides of an intermediate such as compound 52 to afford sulfide 53.
• the benzhydryl group of 53 is removed by treatment with 1-chloroethyl chloroformate in a solvent such as tetrahydrofuran and the resulting amine 54 reacts with an appropriately substituted alkyl bromide in the presence of a mild base such as diisopropylethylamine or Cs 2 CO 3 in an aprotic solvent like CH 3 CN to afford the sulfide 55.
• the sulfide of compound 55 is partially oxidized to the sulfoxide 53.
• the amino group of 56 must be protonated with a strong acid such as methanesulfonic acid in an solvent such as dichloromethane.
• a strong acid such as methanesulfonic acid in an solvent such as dichloromethane.
• the sulfide may be oxidized to the sulfoxide with an oxidant such as periodic acid or by adding a limited amount of a stronger oxidant such as 3-chloroperbenzoic acid.
• the sulfide of compound 55 is completely oxidized to the sulfone 57.
• the amino group of 55 must be protonated with a strong acid such as methanesulfonic acid in an solvent such as dichloromethane.
• a strong acid such as methanesulfonic acid in an solvent such as dichloromethane.
• the sulfide may be oxidized to the sulfone 57 with an excess of an oxidant 3-chloroperbenzoic acid in dichloromethane.
• the nitrogen group of a nitrogen-containing heterocycle such as imidazole or 1,2,4-triazole will displace one or both arylfluorides of an intermediate such as compound 58 at high temperatures in a polar aprotic solvent such as dimethylsulfoxide and in the presence of a base such as potassium carbonate to afford amines 59.
• a nitrogen-containing heterocycle such as imidazole or 1,2,4-triazole
• the bromo group of compound 60 can be selectively replaced by a nucleophile such as Zn(CN) 2 or LADS in the presence of a palladium catalyst such as Pd 2 (dba) 3 to afford the corresponding aryl-substituted analog 61.
• the benzhydryl group of 50 is removed by treatment with 1-chloroethyl chloroformate in a solvent such as tetrahydrofuran and the resulting amine 62 reacts with an appropriately substituted alkyl bromide in the presence of a mild base such as diisopropylethylamine or Cs 2 CO 3 in an aprotic solvent like CH 3 CN to afford 63.
• the amino group of compound 64 (Scheme 22) can be converted to a heterocycle such as 1,3,4-triazole 65 by treatment with a reagent such as N′-[(1E)-(dimethylamino)methylene]-N,N-dimethylhydrazonoformamide in the presence of an acid catalyst at elevated temperature in an inert solvent such as toluene.
• a reagent such as N′-[(1E)-(dimethylamino)methylene]-N,N-dimethylhydrazonoformamide in the presence of an acid catalyst at elevated temperature in an inert solvent such as toluene.
• the benzhydryl group of 65 is removed by treatment with 1-chloroethyl chloroformate in a solvent such as tetrahydrofuran and the resulting amine 66 reacts with an appropriately substituted alkyl bromide in the presence of a mild base such as diisopropylethylamine or Cs 2 CO 3 in an aprotic solvent like CH 3 CN to afford 67.
• a mild base such as diisopropylethylamine or Cs 2 CO 3 in an aprotic solvent like CH 3 CN
• Step 2 Methyl ⁇ 1-[bis(4-chlorophenyl)methyl]-3-hydroxyazetidin-3-yl ⁇ (3,5-difluorophenyl)acetate
• reaction was quenched by addition of 10 mL of saturated NH 4 Cl solution and 20 mL of ether. The layers were separated and the aqueous layer was washed with ether. The combined organic layers were washed with brine, dried over magnesium sulfate and concentrated.
• Step 3 Methyl ⁇ 1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene ⁇ (3,5-difluorophenyl)acetate
• the aqueous extract was washed with ether and the combined organic layers were washed with brine, dried over Na 2 SO4, and concentrated.
• the residue was purified by chromatography on a Waters RCM column (5 micron silica gel, 20 mm ⁇ 10 cm) using a 2:1 mixture of hexane and 5:4:1 hexane-methyl tert-butyl ether-acetonitrile.
• Step 1 Tert-butyl3- ⁇ [methoxy(methyl)amino]carbonyl ⁇ azetidine-1-carboxylate
• Step 4 ⁇ 1-[bis(4-chlorophenyl)methyl]azetidin-3-yl ⁇ (3,5-difluorophenyl)methanone
• Step 5 3- ⁇ 1-[Bis(4-chlorophenyl)methyl]azetidin-3-yl ⁇ -3-(3,5-difluorophenyl)-3-hydroxy-2,2-dimethylpropanenitrile
• Step 6 3- ⁇ 1-[Bis(4-chlorophenyl)methyl]azetidin-3-ylidene ⁇ -3-(3,5-difluorophenyl)-2,2-dimethylpropanenitrile
• Step 1 2- ⁇ 1-[Bis(4-chlorophenyl)methyl]azetidin-3-ylidene ⁇ -2-(3,5-difluorophenyl)ethanol
• Step 2 3- ⁇ 1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene ⁇ -3-(3,5-difluorophenyl)propanenitrile
• Step 3 3- ⁇ 1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene ⁇ -3-(3,5-difluorophenyl)-2,2-dimethylpropanenitrile
• Step 1 Methyl azetidin-3-ylidene(3,5-difluorophenyl)acetate
• Step 2 Methyl ⁇ 1-[1-(4-chlorophenyl)ethyl]azetidin-3-ylidene ⁇ -3-(3,5-difluorophenyl)acetate
• Step 3 1- ⁇ 1-[1-(4-chlorophenyl)ethyl]azetidin-3-ylidene ⁇ -1-3,5-difluorophenyl)-2-methylpropan-2-ol
• the aqueous layer was washed two times with 10 mL ethyl acetate and the combined organic extracts were dried over Na 2 SO 4 and concentrated.
• the residue was purified by reverse phase chromatography (Waters Xterra C18, 19 mm ⁇ 10 mm) using a gradient of CH 3 CN—H 2 O-Et 3 N (20:80:0.1 to 60:40:0.1). Homogenous fractions were pooled and concentrated to afford the title compound.
• Step 1 Methyl ⁇ 1-[(4-chlorophenyl)(phenyl)methyl]azetidin-3-ylidene ⁇ (3,5-difluorophenyl)acetate
• Step 2 1- ⁇ 1-[(4-Chlorophenyl)(phenyl)methyl]azetidin-3-ylidene ⁇ -1-(3,5-difluorophenyl)-2-methylpropan-2-ol
• Step 1 Methyl azetidin-3-yl(3,5-difluorophenyl)acetate
• Step 2 Methyl ⁇ 1-[1-(4-chlorophenyl)ethyl]azetidin-3-yl ⁇ (3,5-difluorophenyl)acetate
• Step 3 1- ⁇ 1-[1(4-chlorophenyl)ethyl]azetidin-3-ylidene ⁇ -1-(3,5-difluorophenyl)-2-methylpropan-2-ol
• Step 1 Methyl ⁇ 1-[(4-chlorophenyl)(phenyl)methyl]azetidin-3-yl ⁇ (3,5-difluorophenyl)acetate
• Step 2 1- ⁇ 1-[(4-Chlorophenyl)(phenyl)methyl]azetidin-3-yl ⁇ -1-3,5-difluorophenyl)-2-methylpropan-2-ol
• Step 1 ⁇ 1-[Bis(4-chlorophenyl)methyl]azetidin-3-ylidene ⁇ (3,5-difluorophenyl)acetaldehyde
• Step 2 ⁇ 1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene ⁇ -1-(3,5-difluorophenyl)propan-2-ol
• Step 1 2- ⁇ 1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene ⁇ -2-(3,5-difluorophenyl)-1-methylethyl 4-nitrophenyl carbonate
• Step 2 2- ⁇ 1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene ⁇ -2-(3,5-difluorophenyl)-1-methylethyl isopropylcarbamate
• the supernatant was decanted and the solids were triturated with two 20 mL portions of dichloromethane and two 20 mL portions of ether.
• the combined organic extracts were washed with saturated aqueous NH 4 Cl solution and brine, dried over Na 2 SO 4 and concentrated to afford the title compound as a mixture of 4 diastereomers.
• the mixture was purified by flash chromatography on silica gel using a step gradient of 3 column volumnes each of 1%, then 2%, then 4%, then 6% ethyl acetate-hexane to afford two diastereomers of the title compound.
• the enantiomers of the faster diastereomer were separated by chromatography on an AD column chiral using 6% isopropanol in heptane.
• Step 1 (1S)-1-(3,5-difluorophenyl)-1-[1-(diphenylmethyl)azetidin-3-yl]-2-methylpropan-2-ol
• the liquid layer was decanted into a 2L separatory funnel and the solids were triturated with three 200 mL portions of dichloromethane.
• the combined organic layers were washed with two 400 mL portions of aqueous NH 4 Cl solution and brine, then dried over Na 2 SO 4 and concentrated to a white solid.
• the residue was purified on ChiralPak AD resin using 5% isopropanol-heptane.
• Step 3 3-((S)-(4-chlorophenyl) ⁇ 3-[(1S)-1-(3,5-difluorophenyl)-2-hydroxy-2-methylpropyl]azetidin-1-yl ⁇ methyl)benzonitrile
• Step 1 (1S)-1-(3,5-difluorophenyl)-1-[1-(diphenylmethyl)azetidin-3-yl]-2-methylpropan-2-ol
• the liquid layer was decanted into a 2L separatory funnel and the solids were triturated with three 200 mL portions of dichloromethane.
• the combined organic layers were washed with two 400 mL portions of aqueous NH 4 Cl solution and brine, then dried over Na 2 SO 4 and concentrated to a white solid.
• the residue was purified on ChiralPak AD resin using 5% isopropanol-heptane.
• Step 2 3-[(1S)-1-(3,5-difluorophenyl)-2-fluoro-2-methylpropyl]-1-diphenylmethyl)azetidine
• Step 3 3-[(1S)-1-(3,5-difluorophenyl)-2-fluoro-2-methylpropyl]azetidine
• Step 4 3-((S)-(4-chlorophenyl) ⁇ 3-[(1S)-1-(3,5-difluorophenyl)-2-fluoro-2-methylpropyl]azetidin-1-yl ⁇ methyl)benzonitrile
• Step 1 3-[(1S)-1-(3,5-difluorophenyl)-2-fluoro-2-methylpropyl]azetidine
• Step 2 3-((S)-(4-chlorophenyl) ⁇ 3-[(1S)-1-(3,5-difluorophenyl)-2-fluoro-2-methylpropyl]azetidin-1-yl ⁇ methyl)benzonitrile
• Racemic 1-(3,5-difluorophenyl)-1-[1-(diphenylmethyl)azetidin-3-yl]acetone was separated into its two component enantiomers by chromatography on a ChiralPak OD column using 1.5% isopropanol-heptane eluant.
• the slower eluting enantiomer was the (+)(S) diastereomer. This material was taken directly in the next step.
• Step 1 3-[(1S)-1-(3,5-difluorophenyl-2-fluoro-2-methylpropyl]-1-(diphenylmethyl)azetidine
• Example 117 The following examples were prepared as described in Example 117 except that the potassium salt of the thiols were used in Step 1 instead of the sodium salts.
• Step 4 1-(3-Bromo-5-fluorophenyl)-1-[1-(diphenylmethyl)azetidin-3-yl]-2-methylpropan-2-ol
• Step 6 3-[(1S)-1-(3-bromo-5-fluorophenyl)-2-fluoro-2-methylpropyl]-1-(diphenylmethyl)azetidine
• Step 8 3-[(S)- ⁇ 3-[(1S)-1-(3-Bromo-5-fluorophenyl)-2-fluoro-2-methylpropyl]azetidin-1-yl ⁇ (4-chlorophenyl)methyl]benzonitrile
• Step 9 3-((1S)-1- ⁇ 1-[(S)-(4-chlorophenyl)(3-cyanophenyl)methyl]azetidin-3-yl ⁇ -2-fluoro-2-methylpropyl)-5-fluorobenzonitrile
• Step 1 4-[3-(1-Azetidin-3-yl-2-fluoro-2-methylpropyl)-5-fluorophenyl]-4H-1,2,4-triazole hydrochloride
• CB1 Cannabinoid Receptor-1 (CB1) Binding Assay
• Binding affinity determination is based on recombinant human CB1 receptor expressed in Chinese Hamster Ovary (CHO) cells (Felder et al, Mol. Pharmacol. 48: 443-450, 1995). Total assay volume is 250 ⁇ L (240 ⁇ L CB1 receptor membrane solution plus 5 ⁇ L test compound solution plus 5 ⁇ L [3H]CP-55940 solution). Final concentration of [3H]CP-55940 is 0.6 nM. Binding buffer contains 50 mM Tris-HCl, pH7.4, 2.5 mM EDTA, 5mM MgCl 2 , 0.5 mg/mL fatty acid free bovine serum albumin and protease inhibitors (Cat#P8340, from Sigma).
• the binding assay for CB2 receptor is done similarly with recombinant human CB2 receptor expressed in CHO cells.
• CB1 antagonist/inverse agonist compounds of the present invention have IC 50 s of less than 1 micromolar in the CB1 binding assay.
• Selective CB1 antagonist/inverse agonist compounds have IC50s 100-fold greater in the CB2 binding assay than in the CB1 assay, and generally have IC50s of greater than one micromolar in the CB2 binding assay.
• CB1 Cannabinoid Receptor-1
• CB1 receptor The functional activation of CB1 receptor is based on recombinant human CB1 receptor expressed in CHO cells (Felder et al, Mol. Pharmacol. 48: 443-450, 1995).
• 50 ⁇ L of CB 1-CHO cell suspension are mixed with test compound and 70 uL assay buffer containing 0.34 mM 3-isobutyl-1-methylxanthine and 5.1 ⁇ M of forskolin in 96-well plates.
• the assay buffer is comprised of Earle's Balanced Salt Solution supplemented with 5 mM MgCl 2 , 1 mM glutamine, 10 mM HEPES, and 1 mg/mL bovine serum albumin.
• the mixture is incubated at room temperature for 30 minutes, and terminated by adding 30 ⁇ l/well of 0.5M HCl.
• the total intracellular cAMP level is quantitated using the New England Nuclear Flashplate and cAMP radioimmunoassay kit.
• the reaction mixture also contains 0.5 nM of the agonist CP55940, and the reversal of the CP55940 effect is quantitated.
• a series of dose response curves for CP55940 is performed with increasing concentration of the test compound in each of the dose response curves.
• the functional assay for the CB2 receptor is done similarly with recombinant human CB2 receptor expressed in CHO cells.
• CB1 antagonist/inverse agonist compounds of the present invention generally have EC50s of less than 1 micromolar in the CB1 functional assay and selective CB1 antagonist/inverse agonists have generally have EC50s of greater than 1 micromolar in the CB2 functional assay.
• mice are used in these studies. After at least 2 days of acclimation to the vivarium conditions (controlled humidity and temperature, lights on for 12 hours out of 24 hours) food is removed from rodent cages. Experimental compounds or their vehicles are administered orally, intraperitoneally, subcutaneously or intravenously before the return of a known amount of food to cage. The optimal interval between dosing and food presentation is based on the half-life of the compound based on when brain concentrations of the compound is the highest. Food remaining is measured at several intervals. Food intake is calculated as grams of food eaten per gram of body weight within each time interval and the appetite-suppressant effect of the compounds are compared to the effect of vehicle. In these experiments many strains of mouse or rat, and several standard rodent chows can be used.
• Rats or mice are used in these studies. Upon or soon after weaning, rats or mice are made obese due to exclusive access to diets containing fat and sucrose in higher proportions than in the control diet.
• the rat strains commonly used include the Sprague Dawley bred through Charles River Laboratories. Although several mouse strains may be used, c57B1/6 mice are more prone to obesity and hyperinsulinemia than other strains.
• Common diets used to induce obesity include: Research Diets D12266B (32% fat) or D12451 (45% fat) and BioServ S3282 (60% fat). The rodents ingest chow until they are significantly heavier and have a higher proportion of body fat than control diet rats, often 9 weeks.
• the rodents receive injections (1 to 4 per day) or continuous infusions of experimental compounds or their vehicles either orally, intraperitoneally, subcutaneously or intravenously. Food intake and body weights are measured daily or more frequently. Food intake is calculated as grams of food eaten per gram of body weight within each time interval and the appetite-suppressant and weight loss effects of the compounds are compared to the effects of vehicle.
• mice mice
• rats Izumi et al, 1997)
• gerbils Varty et al., 2003. It is based on the principle that helplessness takes place when the animal is exposed to a sustained aversive situation. Briefly, when the animal is suspended by its tail it exhibits several escape-oriented behaviors intercalated with bouts of immobility that evolve with time into complete immobility.
• Pretreatment with a wide range of antidepressants such as tricyclic compounds, monoamine uptake blockers, or serotonin reuptake inhibitors (SSRIs)
• SSRIs serotonin reuptake inhibitors
• mice Male mice are housed in a colony room maintained at constant temperature (22° C.) and humidity (30-70%), with food (Harlan Teklad Diet #7012, 5% fat; 3.75 kcal/gm) and water available ad libitum.
• mice are group housed (10/cage) under a reversed light/dark cycle (lights on at 21:00 h, off at 09:00 h) and tests occurred between 10:00 h and 14:00 h.
• the compounds of formula (I) are solubilized into 1% Tween80-saline solution, addition of DMSO may be employed to increase solubility. Compounds are dosed intraperitonieally in a volume of 0.1 mL.
• An automated tail-suspension apparatus (TSE Systems, Bad Homburg, Germany) with a tail hanger connected to a precision linear load cell is used.
• One centimeter of the mouse's tail is inserted into the tail hanger and secured with non-irritating adhesive tape. Mice are suspended by the tail, at a height of 35 cm from the tabletop for 6 minutes.
• the load cell records the mouse's movements and transmits the information to a central computer, which then records the rate of immobility within the course of the session, and calculates total duration of immobility. Total duration of immobility is used as the dependent variable in one-way Analysis of Variance (ANOVA) on treatment.
• ANOVA Analysis of Variance

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